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CTLA-4 Regulates Induction of Anergy In Vivo
Open accessAbstract
The requirement for CTLA-4 during the induction of peripheral T cell tolerance in vivo was investigated using naive TCR transgenic T cells lacking CTLA-4. CTLA-4(-/-) T cells are resistant to tolerance induction, as demonstrated by their proliferative responses, IL-2 production, and progression into the cell cycle. Following exposure to a tolerogenic stimulus in vivo and restimulation in vitro, wild-type T cells are blocked at the late G1 to S restriction point of the cell cycle. In contrast, CTLA-4(-/-) T cells enter into the S phase of the cell cycle, as shown by downregulation of p27(kip1), elevated cdk2 kinase activity, and Rb hyperphosphorylation. Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus.
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T cells that receive antigen with suboptimal CD28 co-stimulation and/or high co-inhibition become anergic, with low IL-2 production and G1/S cell cycle arrest.
“It is generally accepted that T cells that are presented antigen along with suboptimal CD28 co-stimulation [4,5] and/or high co-inhibition [17] result in anergic phenotypes, as characterized by their low IL-2 production and cell cycle arrest at the G1/S phase.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [17]
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2 retracted
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Metadata
- Authors
- Greenwald, R. J., Boussiotis, V. A., Lorsbach, R. B., Abbas, A. K., & Sharpe, A. H.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- St. Jude Children's Research Hospital (US)
- University of California, San Francisco (US)
- Corresponding author
- Sharpe, Arlene H.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 14
- Issue
- 2
- Pages
- 145-155
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W1976945431
- Cited by
- 428
- References
- 48
- Citations by year
- 2025: 8 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 16 · 2020: 12 · 2019: 10 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 17 · 2014: 8 · 2013: 20 · 2012: 13
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32ai010415-02, 5p01ai041584-05)
- National Heart, Lung, and Blood Institute (T32HL007627, T32HL07627)
- National Institute of Allergy and Infectious Diseases (AI40614, AI-35297, P01AI035297, AI 41584, R01AI040614, F32 AI 10415, AI43552)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CTLA-4, T cell anergy, peripheral tolerance, T cell tolerance, cell cycle arrest, p27, CDK2, retinoblastoma protein phosphorylation, IL-2 production, T cell proliferation
- MeSH terms
- Abatacept, Animals, Antigens, Differentiation, Cell Cycle, DNA-Binding Proteins, Immune Tolerance, Interleukin-2, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Transgenic, T-Lymphocytes, Antigens, CD, Cytokines, Apoptosis, Clonal Anergy, Mice, Knockout, Immunoconjugates, Mice, CTLA-4 Antigen, In Vitro Techniques
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